9alpha-halo-delta1-steroids of the pregnane series



United States Patent 3,101,332 9u-HAL0-A -STEROIDS OF THE PREGNANE SERIES Josef Fried, New Brunswick, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y.,. a.

corporation of Virginia No Drawing. Filed Feb. 21, 1955, Ser. No. 489,769

16 Claims. (Cl. 260-23955) This application is a continuation-in-part. of my parent applications, Serial No. 417,489, filed March 10, 1954, Patent No. 2,852,511, and Serial No. 343,243, filedMarch 18, 1953, now abandoned.

This invention relates to the synthesis of valuable steroids.

One otthe objects of this invention is the provision of an advantageous process of preparing steroidsoi. the pregnene (including the allopregnene sand pregnadiene) series, unsaturated in either the 1,2 or 6,7-position, and having. a 9u-halo group, and an ILB-hydroxy or ll-ket'o group.

Another object of this invention is the provision or. steroids, of the pregnene (including the allopregnene and pregnadiene) series, unsaturated in either the 1,2 or 6,7- position, and having a 9a-"halo group and an 11 B-hydroxy or ll-keto-group, which compounds are useful either for their own physiological action or as. intermediates in the preparation of physiologically-active derivatives.

Still another object of .this invention is the provision of steroids of the allopregnane series having bromo substi-tuents in the 2 or 2,4-positions, a 9a-halo group, and an llfi-hydroxy or ll-ketogroup, wherein the halogen has an atomic number no higher than 35,, which compounds are useful-intermediates inone of the processes of this invention,

The preferred 9u-h-alo compounds of this invention are those which are comprehended by the general formula:

wherein one of the positions 1,2 and 6,7 is double-bonded, the 4,5 position-is double-bonded or saturated (preferably doublebonded), and wherein R is hydrogen, R is hydroxy or together R and R is a keto or ketalized keto group (preferably the free keto group), R" is hydrogen, R' is fi-h-ydroxy, or together R" and R' is a keto group, X is an a-halogen group, Z is hydrogen or whydroxy, and Y is hydrogen, hydroxy or acyloxy (e.g. a fatty acyloxy, preferably a lower allcanoyloxy, such as acetoxy, propionyloxy, heptauoyloxy, and caprylyloxy).

Representative A -al-lopregnenes of this invention include, inter alia, the Qua-halo-N-allopregnene-lIdol-3,20- diones (e.g. 9a-fluoro-A -allopregnene-1lfl-ol-3,20-dione), the 9a-haloA -allopregnene-3,l1,20- triones (e.g. 9afluoro-Ahallopregnene-ll1,20-trione), the 9'a-halo-A allopregnene-l1/8,17a-diol-3,20-diones (e.g. 9a-fiuoro-A allopregnene-l1B,17u-dio1-3,20-dione), the 9'a-halo-A allopregnene-1'7a-ol-3,11,20-triones (e.g. 9a-fluoro-A -al' lopregnene-l7a-ol-3,ll-,20 trione), the 9u-h-alo-A -allopreg- Irene-1lfl,21-d-iol-3,20-diones and the 21-esters thereof (e.g. the lower alkanoates, such as the 21-acetate), the 9a-halo-A -allopregnene-21-ol-3,ll,20-triones and their "ice 7 2 ZL-esters, thev 9a-halo-A -a1lopregnene-11-fl,l7a,21-tIiol-- 3,20adio'nes. andtheir 2l.-esters,,;and the 9a-halo-A -allo pregnene-17,2l-di01-3,ll,20 triones and their 21-esters.

Representative A -allopregnenes of this invention correspondto those listed in the preceding paragraph with the double bond. in:the.6,7-position instead of the 1,2-position.

Representative hl -pregnadienes of this invention inclnde, inter alia, the 9p -halo A -pregnadiene-1 113-011 3,20adiones (e.g. 9a-fiuoro A -pregnadiene-1idol-3,20- dione and 9a-chlorovAh -pregnadiene-1l/3-ol-3,20 dione), the I 9u-halo-A -pregnadiene-3,11,20-tripnes (e.g. 9afluoro'A -pregnadiene-3J1,20-trione and 9aChl0TOA pregnadiene-3,l 1,20-trior1e), the9ba-haloA -pregnadiene- 2l-triol-3g20i-dione, 9b -chloro-A f -pregnadiene .1'1'fl ;1'7a, 21'-triol'-3',20-dione 9a-bromo-A pregnadiene-l 1,3,17'11, 21-triol-3,20-dione, and- 9u-iodo-A -pregnadine-1 113, 17a, 2l-triol'-3,20-dione) and the 21-esters thereof (e.g.- 21- lower alkanoyl' esters), and the 9u-halo-A pregnadiene- 1700,21-di01-3,lLZQJIiQfiCS (e.g. 9a-fiuoro A -pregnadiene-17u,21--diol-3,11,20-trione and 9a-chloro-A -preg nadiene-l7a,21 -diol-3,11,20-trione) and the 2l-csters thereof (e.g. 21-lower .alkanoyl esters).

Representative A -pregnadienes of this invention are the steroids corresponding to the A -pregnadienes listed in the preceding paragraph wherein one of the double bonds'is in the 6,7-position rather than the 1,2-position.

The steroids of this invention can be prepared by a number of different processes. A particularly advanta- ,5 geous process for forming the steroids of this invention, 4

consists of using one of the 9a-halo, llfi-hydroxy or 11- -keto steroids disclosed in the [aforementioned applications 1 l-lsetoprogesterones, the 9uhalo-11fi,17m dihydroxy- "progesterones, the Qua-11810 17 a-hydroxy-ll-hetoprogesterones, the ZI-esters of 9ozl1a.l0c0rtic0sterone (e.g. the 21- lower lalkanoyl esters, such as the ZI-acetate), the 21- esters of 9a-halo-11-dehydrocoiticosterone, the 21-esters of 9a-halohydrocortisone, and the 9a-halocortisones, wherein the halogen has an atomic number no higher than 35, preferably no higher than 17. One of these representative steroids is hydrogenated to saturate the 4,5 double bond to form the corresponding al-lopregnane derivative. step in the process may be carried out by means of hydrogen in the presence of a palladium oatalyst with or without a carrier, such as barium sulfate,

charcoal, calcium carbonate, etc. Other known hydrogenation procedures can, of course be used instead. If a 9'a-halo-115-hydroxy or ll-keto allopregnane is used initially, the first step in the process can, of course, be dispensed with and the allopregnane can be used directly in the next step of the process.

According to the next step in the preferred process of this invention, the 9a-halo (wherein the halogen has an atomic number no higher than 35, preferably no higher than 17), 11fi-hydroxy or 1=l-keto allopregnane is then broniinated by means of bromine in a suitable organic solvent such as an acid [c.g. a lower alkanoic acid, such as acetic acid] or an amide [c.g. 1a di(lower alkyl) lower alkanoic acid amide, such as dimethyl formamide]. The structure of the resulting steroid will depend onthe molar ratio of bromine tosteroid employed. If one mole of bromine is used per mole of steroid, a Z-brorno derivative is produced. If two moles of bromine are employed per mole of steroid, however, a 2,4-dibromo derivative is produced as the major product. These brominated rallopregnanes are new compounds, the preferred compounds being those of the general formula wherein Y is hydrogen or acylo-xy (eig. a lower alkan'oyloxy, such as aoetoxy), A is brorno or hydrogen, and R,

R, R", R, X, and Z are as hereinbefore defined.

The brominated allopregnanes of this invention are then dehydrobrominated. This may be done, inter alia, by

With a 2,4-dibrominated derivative, a mixture of A and A derivatives is produced, which may be separated by chromatography, as more fully detailed in the examples following.

The 9a-halo-llB-hydroxy steroids formed by the preterred process of this invention can then either be oxidized with chrornic oxide in the known manner to produce the corresponding 9a-halo-ll-keto derivatives, or they can be reacted with a dehydrohalogenating agent, when the halogen atom is bromine or chlorine, to form the 9,9,11,8-oxido derivative, as more fully disclosed hereinafter. Furthermore, if a 2l-acy1oxy steroid is used as the reactant in the above steps, the esterifying group in the 2l-position can be hydrolyzed by heating the steroid with an alkali metal salt of carbonic acid (eg. potassium bicarbonate or potassium carbonate) for example, in an organic solvent such as an alcohol (eg. methanol) to form the free 21-01.

The steroids of the pnegnane (including the ailopregnene and pregnadiene) series of this invention which are unsaturated in either the 1,2 or 6,7-position, and have a 904-11310 group and an llfi-hydroxy or ll-keto group are physiologically-active compounds which possess glucocorticoid :as Well as mineralocorticoid activity. Thus, the new steroids of this invention can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatornyositis, or in the same manner as desoxycorticosterone in the treatment of Addisons disease or adrenal insufliciencies. The dosage for such administration is of course dependent on the relative activity of the compound; thus, where the steroid derivative has thirty times the activity of cortisone, the dosage of the former to be employed should be one-thirtieth of the employed dosage of the latter.

For the purpose of illustrating the preferred process of this invention, reference is made to the following schematic analysis employing the ZI-acetate esters of 9ahalo-hydrocortisone and 9ot-halo-cortisone as starting materials:

ornoooon; cnioooorn I -OH (EH20 O OCH:

and

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 (a) 9a-Fluoroallopregnane 11t3,17u,21-Tri0l-3,20 Dione 21 -Acetate (V) from 9a-Fluorohydrocortisone Acetate (I) -A solution of 2.5 grams of 9ot-fluorohydrocortisone acetate in 75 ml. of 95% alcohol is agitated in an at.- mosphere of hydrogen at room temperature and ordinary pressure in the presence of 500 mg. of palladium on barium sulfate catalyst. After the absorption of 160.5 ml. of hydrogen, the reduction comes to a standstill. The catalyst is filtered off and the 9'a-fluoroallopregnane- 1'1;3, 17a,2'l-triol-3,20-dione 21-acetate crystalliied by sugc es sive concentrations of the filtrate. A total of about 2.17 grams of material approximately (87% of theory) is obtained, having the following properties: M.P., about 236-237; [0c] +66 (c., 0.96 in acetone); x33 2.82;, 2.97,. (OH), 5.75,. (ZI-aoetyl), 5.81 keto), 5.97a (3-keto); N25,; 293 (e=1l0) Analysis.Calcd. for C H O F (424.49): C, 65.54; H, 7.87. Found: C, 65.34; H, 7.69.

Essentially the same result is obtained when the hydrogenation is conducted in ethyl acetate. 9a-fluoroallopregnaneal1[3,-l7a,2l-triol-3,20 dione 21-acetate crystallizes with ethyl acetate of crystallization, and it is desirable in this case to recrystallize from alcohol in order to obtain it free of the ethyl acetate. Other Zl-esters of 9a-fiuorohydrocortisone such as the propionate .valerate, 'or caprylate, can, of course, be substituted forthe 21- acetate in Example '1.

Similarly, if 9a-ch1orohydrocortisone acetate ll), 9afiuoroeortisone acetate (III), or 9wchlorocortisone acetate (IV) is substituted for 9a-fiuorohydrocortisone acetate in the procedure of Example 1, 9q-chloroallopregnane-llfi,17a,21-triol-3,20-dione ill-acetate (VI), 90 fiuoroallopregnane-17a,21adio1-3,11,20-trione 21-acetate (VII), and 9a-chloroallopregnane-170 ,21-diol- 3,11,20- trione Zl-acetate (VIII) are formed, respectively.

(b) Z-Bromo-Qa Fluoroallopregnane 11,/3,17a,21-Iri0l- 3,20-Di0ne ZJ-Acetate (IX) from 9a-Fluor0allopregnane-I] 5,17u,21-Triol-3,20-Di0ne ZZ-ACetate (V) A solution of 424 mg. of 9a-fiuoroallopregnane-1lfi,

l7a,2l-triol-3,20-dione 21-acetate in 25 m1. of glacial aceomoooon;

tic acid is treated with a few drops of 1.0 N HBr in acetic acid, and shortly thereafter with a solution of 160 mg. of bromine in 2 ml. of glacial acetic acid. To the colorless solution is added 150 mg. of solid potassium acetate, and the mixture is concentrated to small volume in vacuo. Water and chloroform are added, and after separation of the layers, the chloroform extract is washed with sodium bicarbonate solution and with water; and the 2-bromo-9u-fluoroallopregnane-l1.,B,17a,21 trial-3,20-dione Q21 acetate (IX) is recovered by evaporation of the solvent. v

(c) 9o -Fluoro A All0pregnene-11/3,17a,21-Triol-3,20-

Dione 21-Acetate (XIV) from 2-Br0m0-9u-Flu0r0-Allopregnane 11,6,1 711,21 Trial-3,20-Dione 21 -Acetate 1 A solution of the resulting residue (IX) obtained in section-(b) in 5 of collidine is refluxed tor 30 minutes und r nitrogen, and then treated with chloroform and suflicient 1 N sulfuric acid to remove all the collidine from the chloroform solution. The chloroform solution is washed with sodium bicarbonate solution and with water and the solvent evaporated in vacuo. Addition of ethyl acetate to the residue (about 421 mg.) leads to crystallization'o f the desired 9a-fluoro-N-allopregnene- 11B,17 t,21-triol-3,20-dione 21-acetate which, after recrystalliz ati'on from ethyl acetate, has the following properties: M.P. about 237439"; +98 (c., 1.06 in acetone); g I

215... 8ml, A2352 3.00 4 (acetyl); 5.80 (20-keto); 5.97;, 6.11 (A -3-keto) Anglysis,-Calcd. for 0 11 0 1 422.47 c, 65.39; H, 7.39. Found: C, 65.56; H, 7.19.

This substance possesses about three times the activity of cortisone acetate in the rat liver glycogen test. 9afluoro-N-allopregnene-l 118,17a,21-triol-3,20-dione 21-acetate can also be prepared by the processes of the following two examples:

tor. The crude dinitrophenylhydrazone of 9oc-fluoro-A allopregnene-llfi,l7u,2l-triol-3,20-dione 21-acetate is decomposed with pynuvic acid in the manner described by Mattox and Kendall, J. Biol. Chem. 185, 601 (1950). The resulting substance is identical in all respects with the product of Example 1.

EXAMPLE 3 A solution of 500 mg. of 2-bromo-9a-fiuoroallopregnane-llfl,l7u,2l-triol-3,20-dione ZI-acetate (IX) and 130 mg. of lithium chloride in ml. of dimethylformamide is heated for 2 hours on the steam cone. The mixture is diluted With water, and the resulting suspension is extracted with chloroform. The chloroform extract is washed with water, sodium bicarbonate and again with water and the solvent evaporated in vacuo. The residue, on crystallization from ethyl acetate, furnishes pure 9a-fluoro-n -allopregnane-l 1p, 1 711,2 1 -triol-3,20-dione 21- acetate having the properties shown in Example 1.

Similarly, if 9a-chloroallopregnane-ll/8,17a,2l-triol-3,

20-dione 2l-acetate (VI), 9a-fi-uoroallopregnane-l7a,21- diol-3,l1,20-tri-one Zl-acetate (VII), or 9u-chloroallopregnane-17a,2l-diol-3,l1,20-trione 2l-acetate (VIII) is substituted for 9ot-fiuoroallopregnane-1l 3,l7a,2l-triol-3, 20-dione 21-acetate (V) in section (b) of Example 1, the intermediate steroids produced, respectively, are 2- bromo-9 n-chloroallopregnane-l 1B, 17a,2 l-triol-3,20-dione ZI-acetate (Xa), 2-br0mo-9a-fluoro-allopregnane-17u,2ldiol-3,ll,20-trione Zl-acetate (XIa), and 2-b1OHTO-90L- chlor0allopregnane-17 a,2 1-diol-3,l 1,20-trione 21-acetate (XIIa). These intermediates can then be converted to 9ot-ehlor-o-A -allopregnene-l1fi,l7a,21-triol-3,20-dione 21- acetate (XV), 9a-fiuoro-A -allopregnene-l7a,21-diol-3,11, 20-trione 21-acetate (XVI), and 9u-chloro-A -allopregnene-l7oc,21-diol-3,11,20-trione 2l-acetate (XVII), respectively, by the processes of Examples 1 (section c), 2 or 3.

EXAMPLE 4 9u-Flu0ro-A -Pregnadiene 1 118,1 7 11,21 -Tri0l-3,20-Dione 21 -Acetate (XVIII) and 9a-Flu0ro-A -Pregnadiene- ]1 8,17a,21-Triol-3,20-Dione 21 -Acetate (XXII) from 9a-Flu0roallopregnane-1 1B,] 7 a,21 Trial 3,20-Di0ne ZI-Acetaze (V) To a solution of 2.120 grams of 9a-fluoroallopregnane- 11 3,l7oz,2l-triol-3,20-dione 21-acetate in 100 ml. of glacial acetic acid is added 0.05 ml. of 1.3 N Ihydrobromic acid in acetic acid, and then dropwise with stirring a solution of 1.52 g. of bromine in 19 ml. of acetic acid. A-fter standing at room tempe-nature for one hour, 1.1 g. of potassium acetate is added, and the mixture concentrated in vacuo to small volume. After the addition of water, the suspension is extracted with chloroform and the chloroform solution washed with water, sodium bicarbonate solution and again with water. Removal of the solvent in vacuo leaves the crude 2,4-di-bromo-9afluoroallopregnane-l1B,17a,21-triol-3,20-dione 21-acetate (X) as an amorphous residue, which is debrominated with col-lidine without further purification. For this purpose it is dissolved in 25 ml. of coll-idine and refluxed for 30 minutes in an atmosphere of nitrogen. The mixture is diluted with chloroform and the collidine removed by extraction with dilute sulfuric lflCld. After washing with sodium bicarbonate solution and water, the chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in 16 ml. of chloroform and the resulting solution diluted with 48 ml. of benzene. The mixture is centrifuged and chromatographed on 30 g. of sulfuric acid-washed alumina. Elution of the column with 1 part of chloroform and 3 parts of benzene produces a mixture of by-products, which is followed by 9a-fluoro-n -pregnadiene-1118,17a,2ltriol-3,20-dione 2l-acetate (XXII) when the eluting fluid is changed to a mixture of equal parts of chloroform 8. and benzene. Recrystallization of the combined fractions from ethyl acetate afiords the pure substance having the following properties: M.P. about 209-211"; [@1 +l39 (c., 0.76 in CHCI Nuinl Am; 281 mu (e=23,000); mm 286p, 3.02 1. (OH), 5.76;; (acetjyl), 5.80;. (ZO-keto), 6.07;, 6.12 6.20; (A -3-ketone 241-244"; +99 (c., 0.34 in acetone);

WAS; 238 mp (=14,700); Ami? 2.93 3.02 1 (OH), 5.76;; (2.08133 1), 5.85;; (20-11600), 6.02 6.19 6.2611. (A -34(8- tone Analysis.-Calcd. for C I-I O F (420.46): C, 65.70; H, 6.95. Found: C, 65.88; H, 7.20.

fiuoro A pregnadiene 11fi,l7oc,21 triol 3, ZO-dione 2l-acetate possesses about 30 times the activity of cortisone acetate in the rat liver glycogen assay.

90c fluoro A pregnadiene 11fl,17a,21 triol 3, ZO-dione Zl-acetate and its M' -isomer can also be produced by the procedure of the following example:

EXAMPLE 5 A solution of 600 mg. of 2,4-dibromo-9u-fiuoroallopregnane-l118,l7u,2l-triol-3,20-di0ne 2l-acetate (X) and 255 mg. of lithium chloride in 5 ml. of dimethylformamide is heated on the steam cone for 2 hours in an atmosphere of nitrogen. The mixture is diluted with water and the resulting suspension extracted with chloroform. The chloroform solution is washed with water, sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue, on chromatography as described in Example 4, furnishes the desired substances in pure form.

90; fluoro A pregnadiene-llB,17a,2l-triol 3, 20-dione 2l-acetate is also obtained when 2,4-dibromo- 9oz-fluoroallopregnane-1115,17ot,2l-triol-3,20-dione 2l-acetate is treated with dinitrophenylhydrazine (or with semicarbazide) as described in Example 2 for the corresponding monobromo compound, and the resulting dinitrophenylhydrazone (or semicarbazorie) is decomposed with 90% pyruvic acid.

Similarly, if 9a-:chloroallopregnane-llB,17a,2l-trio1-3, 20-dione 2l-acetate (VI), 9a-fluoroallopregnane-17a,2ldiol-3,11,20-trione ZI-acetate (VII), or 9a-chloroallopregnane-17a,21-diol-3,l1,20-trione 2l-acetate (VIII) is substituted for 9a-fluoroallopregnane-11,8,17a,21-triol-3, 20 di one 21-acetate in the process of Example 4, the intermediates 2,4-dibromo-9a-chloroallopregnane-11fi,17a, 2l-tri'ol-3,20-'dione Zl-acetate (XI), 2,4-dibromo-9a-fluoroallopregnane :,21 rdiol 3,11,20-trione ZI-acetate (XII), and 2,4-dibromo-9a-chloroallopregnane-l7a,2l-di- 0l-3,11,20-trione ZI-acetate (XIII) are obtained, respectively. These djlbrominated intermediates can then be converted to a mixture of their respective A -pregnadienes (XIX to XXI) and n -pregnadienes ()QGII to XXV) by the procedures of Examples 4 and 5.

Furthermore, if another 9a-halo steroid of the pregnane series is substituted for the 9m-halohydrocortisones (acetate) and 9a-halocortisones (acetate) employed as described hereinbefore, the corresponding A A and A derivatives are obtained. Thus, 9a-fluorocorticosterone acetate yields 9a-fluoro-A -allopregnene-11,8,21-

tate, 9a-chloro-A pregnadiene-21-ol-3,11,20-trione 21- M acetate and 9OPChIODO-A -PICgIIEdi6IIB-Z1-01-3,11,20%1'1- one 21-acetate; 9a-fl110r0-1 1B,l7a-dihydroxyprogesterone yields 90: fiuoro-N-allopregnene-l1B,17wdiol-3,20-dione, 9oz fluoro h -pregnadiene-l1fl,17a diol-3,20-dione and 90; fluoro A -pregnadiene-l1 8,17a-diol-3,20-dione; 9afiuoro-llp-hydroxyprogestrone yields 9a-fluoro-A -allopregnene 11 3 ol-3,20-dione, 9a-fiuoro-A -pregnadiene- 11B-'ol-3,20-dione, and 9a-fluoro-A -pregnadiene-115- 3,20-dione; 9a-chloro-1lp-hydroxyprogesterone yields 9achloro-A -allopregnene-l15-ol-3,20-dione, 9or-chloro-A pre'gnadiene-11 3 ol-3,20-dior1e and 9u chloro-A -pregnadiene-l1fi ol-3,20-dione; and 9a-fluoro-11-ket0progesterone yields 9a-fiuoro-A -allopregnene-3,11,20-trione, 90cstluoro-h pregnadiene-l11,20-trione and 9a-fluoro-A pregnadiene-B, 1 1 ,20-trione.

The 21-esterifying group may be hydrolyzed by heating the steroid with an alkali metal salt of a weak acid (e.-g. potassium carbonate or potassium bicarbonate) in an organic solvent (erg. methanol) to yield the free 21- 01. By this method the 9tx-halo-A -(or A or Mm-a1- lopregncne-(or pregnadiene) l1B,17u,21-trio1-3,20-dione- (or 17a,21-diol-3,11,20-trione) ZI-acetates are converted to the free 21-ols.

If an llfi-hydroxy steroid is used as the starting material, the resulting 11 fi-hydroxy products may be oxidized to the corresponding 11-keto derivatives by treating the products with an oxidizing agent such as chromic oxide.

The 9a-bromo A A and A steroids of this invention (and 9a-iodo derivatives) are preferably prepared indirectly from corresponding A (or A or A 9achloro llfl-hydroxy steroids by way of the A (or A, or A) 9'5,11,B-oxido intermediates of this invention, the preferred 95,11B-oxido intermediates beingthose of the general formula HrY wherein one of the positions 1,2 and 6,7 is doublebonded, the 4,5 position is dou'bleabonded or saturated (preferably doublelbonded), and wherein R, R Z and Y are as herein-before defined. Thus, the A (or A or A) 9a-chloro llfi-hydroxy steroid is reacted with a salt of a strong [base and a weak acid, such as an alkali metal carbonate (e.g., potassium carbonate) or an alkali metal alkoxide (e.=g. sodium methoxide), and the corresponding A (or A or A) 913,1113-oxid1o compound thus formed is then reacted with a hydro-gen halide (e.g. hydrobrromic acid or hydroiodic acid) toform the corresponding A (or A or A) 9a-halo llfi-hydroxy de- 10 rivative. The series of steps can (be represented by the fioll'owing schematic analysis and examples:

CHzOOOCH It should be noted that if the 9u-Chl0f0 steroid has an esterified hydroxy group inthe 21-position, this group is hydrolyzed, and a free 21-01 is produced. The 21- hydro-xy group can, however, later be esteriiied by treatment with the desired acyl halide or acid anhydride to form either a ZI-esterified -9,8,1l;8-oxid-o or 21-esterified 9ot-halo derivative.

EXAMPLE 6 (a) 9}9,11,B Oxido-N-Allopregnene-I 7a,21-Di0l-3,20-Dione (XXVI) from '9a-Chloro-A -Allopregnene-Ilfi, 17a,21,Tri0 l,3,20-Dione 21-Acetate (XV) To a solution of mg. of 9u-chloro-A -allopregnene- 11B,170:,21-11101-120-(110116' 21-acetate in 10 ml. of methanol is added a solution of 100 mg. of potassium carbonate in 0.5 ml. of oxygen-free water. Nitrogen is passed through the resulting solution for 5 minutes, and the mixture is allowed to remain at room temperature for three hours. Acetic acid is added to neutralize the carbonate, and after the addition of 5 ml. water, the methanol is removed in vacuo. The remaining aqueous suspension is extracted with chloroform, the chloroform extract washed with water and dried over sodium sulfate. Evaporation of the solvent leaves a residue of the desired 93,1 lfi-eporzide.

In a similar manner, flay using 9'a-chloro-A -pregnadiene-l1,8,17u,21rtriol-3,204dione ZI-acetate (XIX) or (b) 904 Bromo N-Allopregnene-l 118,1 7a,Z1-Tri0l-3,20- Dione (XXIX) from 9B,11B-Oxido-N-Allopregnenel7oc,21-Di0l-3,20-Di0ne (XXVI) To a solution of 25 mg. of 9 3,1lfi-oxido-A -allopregnene-17a,2l-diol-3,20+dione in 1 m1. of chloroform is added with shaking at room temperature 0.04 ml. 30% hydrobromic acid in glacial acetic acid. After 10 minutes, 10 ml. of chloroform is added, and the mixture is extracted with dilute sodium bicarbonate and with water. The chloroform solution is dried over sodium sulfate, and evaporated to dryness in vacuo; and the residue, 9a bromo-N-allopregnene-l1,8,l7a,2l-triol-3,20-dione, is crystallized from acetone.

In a similar manner, by substituting 60% aqueous hydroiodic acid for hydrolbromic acid in section (b) of Example 6, the corresponding 9'a-iodo compound (XXX) is formed.

Similarly, the 9,6,1l5-oxido steroids XXVII and XXVIII can be converted to the corresponding 9abromo and 9a-iodo derivatives (XXXI to XXXIV) by the method of Example 6. Furthermore, the 9a-lbronro and 9u-iodo llfi-hydroxy derivatives obtained can be oxidized to the corresponding 9u-brorno or 9a-i'odo 11-keto deriv-.

atives by reaction with chromic acid.

Another utilizable process for preparing the steroids of this invention comprises brominating an lla-hydroxy steroid of the allopregnane series (after hydrogenating the steroid, if there is unsaturation in the 4,5-position, as for example by means of hydrogen in the presence of a palladium catalyst with or Without a carrier such as barium sulfate, and separating the allopregnane isomer from the ooproduced pregnane derivative) to form either a 2-mono'bromo or 2,4-dibromo derivative. Suitable starting steroids for this process include lla-hydroxyprogesterone, 11ot,l7a dihydroxyprogesterone, the 21- esters (e.g. 21-acetate) of epicortieosterone, and the 21- esters (e.g. 21-acetate) of A -pregnene-1lu,l7a,2l-triol- 3,20-dione (also known as epi F), as Well as the 4,5-dihydro derivatives of each of these. These bromo derivatives are then dehydrobrominated by heating with a base, such as collidine with or without a lithium halide salt, or with a lithium halide salt in a lower fatty acid amide (e.-g. dimethylformamide) to form the corresponding A -allopregnene derivative, when a 2-monobromo steroid is used, and a mixture of the corresponding A and A -pregnadiene derivatives, when a 2,4-dibromo derivative is employed. These A A and A -11u-hydroxy derivatives are then subjected to the conversion disclosed for lla-hydroxy derivatives in said applications, Serial Nos. 417,489 and 343,243, to obtain the compounds of this invention. Thus, the llu-hydroxy allorpregnenes or pregnadienes, unsaturated in either the 1,2 or 6,7-position, are reacted with a sulfonyl halide, such as tosyl chloride, to form the corresponding Ila-sulrfonyloxy (e.-g. lloc-tOSYlOXY) derivatives, which in turn are heated, for example, with sodium acetate and acetic acid, to form the corresponding A -derivatives. These derivatives are then hydroxybrominated, with say N- brornoacetamide, to form the corresponding 9ubromollp-hydroxy derivatives, which in turn can be oxidized with chromic oxide to form the corresponding 9ot-bromoll-keto derivatives, or can be converted with potassium acetate to the corresponding 95,115-oxido: derivatives. These 9 8,1lfi-0xido derivatives can then be reacted with a hydrogen halide, such as hydrofluoric acid, hydrochloric acid or hydroiodic acid to form the corresponding 909-112110- 11,8-hydroxy derivatives, and these derivatives can then be oxidized with chromic oxide to the corresponding 9ahalo-l l-keto derivatives.

The preparation of 1la-hydroxy-A -pregnadienes or 11a-hydroxy-A -pregnadienes utilizable in the foregoing process of this invention is illustrated by the following example, wherein A -pregnadiene-l1a,17a,21-triol-3,20- dione 2l-acetate and A -pregnadiene-l1a,l7a,2l-triol-3,

20-,dione Zl-acetate are prepared from M-pregnene-lla, 17a,2l-triol-3,20-dione.

EXAMPLE 7 A solution of 8.0 g. of o -pregnene-l1a,17a,21-triol-3, ZO-dione in 500 ml. of alcohol is shaken in an atmosphere of hydrogen 'at room temperature and ordinary pressure in the presence of l g. of a 5% Pd on charcoal catalyst. After the absorption of 630 ml. of hydrogen, the reduction comes to a standstill. The catalyst is filtered off and the solvent removed completely in high vacuum. The mixture of pregnane-lla,17a,21-triol-3,20- dione and the corresponding allopregnane is separated chromatographical-ly as described in US. Patent No. 2,659,744.

720 mg. of the allopregnan'e-l1a,l7a,2l-triol-3,20-dione thus recovered is acctylated in the 21-position only by dissolving it in 5 ml. of dry pyridine and adding to the solution 210 mg. of acetic anhydride. After 18 hours at room temperature, the mixture is diluted with water and chloroform. 'Ihe chloroform extract is washed with water, 1 N hydrochloric acid, sodium bicarbonate and again with Water, dried over sodium sulfate and the solvent removed in vacuo.

The resulting allopregn'ane-llu,l7u,21-triol-3,20-dion'e 21-acetate is dissolved in 40 ml. of glacial acetic acid and to the solution isladded slowly with stirring 7.6 ml. of a solution of bromine in acetic acid (80 mg. Br /rnl.). When all the bromine has been adsorbed, 370 mg. of solid potassium acetate is added and the mixture concentrated to a small volume in vacuo. Water and chloroform is added and after separation of the layers, the chloroform extract is washed with sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue, consisting essentially of 2,4-dibromo-allopregnane-l1a-l7a,2l-triol- 3,20-dione 21-acetate, is dissolved in 10 ml. of collidine and the resulting solution boiled under reflux for hour in an atmosphere of nitrogen. The mixture is then treated with chloroform and sufficient 1 N hydrochloric acid to remove all the collidine from the chloroform solution and the latter Washed with sodium bicarbonate solution and water. Evaporation of the solvent in vacuo leaves a residue, from which the desired A -pregnadiene-l1a,17u,2l-triol-3,20-dione 2l-acetate is separated by chromatography on 12 g. of sulfuric acid-Washed alumina. For this purpose, the residue is dissolved in 4 ml. of chloroform and 12 ml. of benzene, poured on the column' and the latter eluted with a solvent mixture containing 1 volume of chloroform and three volumes of benzene, which removes some amorphous material. When the eluate is changed to chloroform A -pregnadiene-l1a, l7a,21-triol-3,20-dione 21-acetate is eluted, followed by A -pregnadiene-llu,l7a,2l-triol3,20-dione 2l-acetate.

The A -pregn-adiene-1la,l7u,2l-triol-3,20-dione 21- acetate is characterized further by conversion into its 21-diacetate, having the following properties: M.P. about 233-234"; [0c] |97 (0., 0.70 in chloroform).

A313, 244 m (e=16,400); Xfigif 3.08m 5.75 (acetyl), 5.79 (20-keto), 6.05 623 (A -3-ketone) The invention may be variously otherwise embodied within the scope of the appended claims.

I claim:

1. A steroid of the formula CHzY wherein Z is selected from the group consisting of hy- CHzY drogen and u-hydroxy; and Y is selected from the group consisting of hydrogen, hydroxy, and lower alkanoyloxy.

7. A compound selected fromthe class consisting of 9,6, 1 1 fi-oxido-A -allopregnene-17 (1,2 1-diol-3,20-dione and 21-lower alkanoyl esters thereof.

8. 9a-fluoro-A -3,11,20-triketo-17a hydroxy 21-1ower alkanoyloxy-allopregnene.

9. 9u-fluoro-A 3,11,20-triketo-17a,21-dihydroxy allopregnene.

10. 9a-fluoro-A -3,11,20-triketo-17a,21-dihydroxy allopregnene ZI-acetate.

11. 9u-fluoro-A -3,20-dik-eto-1173,17a dihydroxy 21- lower allcanoyloxy-allopregnene.

12. 9aflIlO1'0-A -3,20-'dik6tO 11fi,17a,21 trihydroxyallopregnene.

13. 9a-fluoro-A -3,20-diketo 11 5,17a,21 t-rihydroxyallopregnene 21-acetate.

14. A steroid selected from the group consisting of ll-keto and 11B-hydroxy-9a-halo-A -pregnenes having a keto group at the 3- and 20-positions, a member of the group consisting of H and OH at the 170t-POSitiOIl, a member of the group consisting of hydroxy and lower alkanoyloxy at the 21-position and characterized by the presence of a double bond only in the 1-position.

15. A steroid selected from the group consisting of ll-keto and llfi-hydroxy allopregnanes having a keto group at the 3- and 20-positions, a member of the group consisting of H and OH rat the Noe-position, a member of the group consisting of hydroxy and lower alkianoyloxy at the 21-position and characterized by the presence of a Ibromine atom .at the 2-position and a halogen having an (atomic number no higher than in the 9u-position.

16. A steroid selected from the group consisting of A -pregnenes having a keto group at the 3- and 20-positions, a member of the 'group consisting of H and OH at the 17a-position, a member of the group consisting of hydroxy and lower alkanoyloxy at the 21-position and characterized by the presence of a 9,8,11,8-oxido group and a double [bond only in the 1-position.

References Cited in the file of this patent UNITED STATES PATENTS 

6. A STEROID OF THE FORMULA 